Lu Shun, Zhang Jie, Zhou Zhen, Liao Mei-Lin, He Wei-Zhong, Zhou Xiao-Yan, Li Zi-Ming, Xiang Jia-Qing, Wang Jie-Jun, Chen Hai-Quan
Shanghai Lung Cancer Center, Shanghai Chest Hospital, Jiao Tong University, Shanghai, P.R. China.
Oncol Rep. 2008 Sep;20(3):581-7.
Zoledronic acid (Zometa, ZOL) and cytotoxic chemotherapy agents have been reported to have synergistic antitumor activities. However, there is limited data on the effects of combination therapies on the development of bone metastasis in animal models of lung cancer. The purpose of this study was to establish a human lung adenocarcinoma cell line with high bone metastatic potential in an immunodeficient mouse model and to evaluate the synergistic inhibitory activity of zoledronate and paclitaxel (P) on bone metastasis in nude mice. A human lung adenocarcinoma cell line with high bone metastatic potential (SPC-A1-BM) was established by 10 rounds of in vivo selection. Cells were inoculated into the cardiac ventricle of NIH-BNX mice, which were treated 8 days later with: ZOL (0.2 mg/kg s.c. twice weekly) alone, P (6.0 mg/kg every week, i.p.) alone, P + ZOL, or vehicle (10 mice per group). Tumor growth was evaluated with bone scans, X-rays and in situ immunohistochemistry. Serum n-telopeptide of type I collagen (NTX) was measured by ELISA. Survival was assessed using the Kaplan-Meier method. Bone scan, radiographic and histological assessments revealed fewer bone metastases in all treatment groups vs. vehicle, with P + ZOL significantly reducing the incidence of bone metastases detected by bone scans (P=0.020) and X-rays (P=0.036). A histological analysis revealed marginal differences in the number of bone metastases between P + ZOL and vehicle (P=0.058). There was a trend towards differences in survival between the groups (P=0.1511) and survival was significantly longer for the P + ZOL group vs. vehicle (P=0.022). Compared with vehicle and ZOL alone, cancerous cells in the bone of mice treated with P + ZOL expressed higher levels of Bax and lower levels of Bcl-2 and Bcl-xl. ZOL produced a trend towards reduced NTX levels vs. vehicle and P + ZOL produced a profound reduction in NTX vs. vehicle (P=0.022). The results of this study indicated that zoledronate enhanced the efficacy of paclitaxel synergistically, by reducing the incidence of bone metastasis from lung cancer and prolonging survival in a mouse model of non-small cell lung cancer with a high potential for metastasis to bone.
唑来膦酸（择泰，ZOL）与细胞毒性化疗药物据报道具有协同抗肿瘤活性。然而，关于联合疗法对肺癌动物模型中骨转移发展影响的数据有限。本研究的目的是在免疫缺陷小鼠模型中建立具有高骨转移潜能的人肺腺癌细胞系，并评估唑来膦酸盐与紫杉醇（P）对裸鼠骨转移的协同抑制活性。通过10轮体内筛选建立了具有高骨转移潜能的人肺腺癌细胞系（SPC-A1-BM）。将细胞接种到NIH-BNX小鼠的心室，8天后用以下方法处理：单独使用ZOL（0.2mg/kg皮下注射，每周两次）、单独使用P（6.0mg/kg每周一次，腹腔注射）、P+ZOL或赋形剂（每组10只小鼠）。通过骨扫描、X射线和原位免疫组化评估肿瘤生长。通过ELISA测量血清I型胶原N-端肽（NTX）。使用Kaplan-Meier方法评估生存情况。骨扫描、影像学和组织学评估显示，与赋形剂组相比，所有治疗组的骨转移均较少，P+ZOL显著降低了骨扫描（P=0.020）和X射线（P=0.036）检测到的骨转移发生率。组织学分析显示，P+ZOL组与赋形剂组之间骨转移数量存在边际差异（P=0.058）。各组之间生存存在差异趋势（P=0.1511），P+ZOL组的生存期明显长于赋形剂组（P=0.022）。与赋形剂组和单独使用ZOL组相比，P+ZOL处理的小鼠骨中的癌细胞Bax表达水平较高，Bcl-2和Bcl-xl表达水平较低。与赋形剂组相比，ZOL使NTX水平有降低趋势，而P+ZOL与赋形剂组相比使NTX水平显著降低（P=0.022）。本研究结果表明，唑来膦酸通过降低肺癌骨转移发生率并延长具有高骨转移潜能的非小细胞肺癌小鼠模型的生存期，协同增强了紫杉醇的疗效。
